Glycosaminoglycan Replacement Therapy with Intravesical Instillations of Combined Hyaluronic Acid and Chondroitin Sulfate in Patients with Recurrent Cystitis, Post-radiation Cystitis and Bladder Pain Syndrome: A Narrative Review.

Defects in the glycosaminoglycan layer (GAG) of the bladder mucosa have been identified as a significant contributor to the pathogenesis and clinical progression of chronic inflammatory diseases of the bladder, such as post-radiation cystitis, bladder pain syndrome and recurrent urinary tract infections. This narrative review aims to explore the contemporary evidence on the role of GAG reconstitution with intravesical installations of hyaluronic acid and chondroitin sulfate in the management of those patients, with a goal to provide valuable insights for clinical practice. The reviewed studies consistently demonstrate that GAG reconstitution can result in varying degrees of clinical improvement in patients with post-radiation cystitis, bladder pain syndrome and recurrent urinary tract infections, and is associated with a very favorable safety profile. While the available evidence is growing, its level is still limited, mainly by relatively low number of randomized controlled trials, with small sample sizes. Further research with larger, well-designed trials is needed to solidify the findings and optimize the clinical application of GAG reconstitution.

Liquid levothyroxine improves thyroid control in patients with different hypothyroidism aetiology and variable adherence - case series and review.

It is estimated that hypothyroidism treatment may be either suboptimal or excessive in about 32-45% patients treated with L-thyroxine (LT4). There are multiple possible causes of poor control of hypothyroidism, including narrow LT4 therapeutic index, food and drug interactions, comorbidities, and patient non-adherence. Some of these obstacles could possibly be overcome with the novel liquid LT4 formulation. Liquid LT4 reaches maximum blood concentration about 30 minutes faster than the tablet form. Faster pharmacokinetics might lead to more efficient LT4 absorption, as suggested by a recent real-world study in patients with primary and central hypothyroidism. Liquid LT4 treatment led to increased free thyroxine (FT4) and sex hormone binding globulin (SHBG) with decreased low-density lipoprotein (LDL) cholesterol concentration and substantially improved quality of life for the patients. Herein we present a series of 31 patients with hypothyroidism of different aetiologies treated with the novel liquid LT4 formulation in standard clinical care in light of the latest scientific publications on liquid LT4 formula. We observed normalization of thyroid function tests shortly after introduction of liquid LT4, irrespective of concurrent diseases or concomitant medications that could diminish LT4 absorption. In more detail, the treatment with liquid LT4 managed to normalize thyroid-stimulating hormone (TSH) concentrations in patients without any known causes of LT4 absorption disturbances, as well as in those with malabsorption: with gastric bypass, partial small and large intestine resection, scleroderma, gluten intolerance, celiac disease, atrophic gastritis, and polytherapy. In conclusion, considering many factors disturbing LT4 absorption, hypothyroidism therapy with liquid LT4 seems to be a particularly effective option.

Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks.

The neuregulin 1 (NRG1) ErbB4 module is at the core of an "at risk" signaling pathway in schizophrenia. Several human studies suggest hyperstimulation of NRG1-ErbB4 signaling as a plausible pathomechanism; however, little is known about the significance of stage-, brain area-, or neural cell type-specific NRG1-ErbB4 hyperactivity for disease-relevant brain endophenotypes. To address these spatiotemporal aspects, we generated transgenic mice for Cre recombinase-mediated overexpression of cystein-rich domain (CRD) NRG1, the most prominent NRG1 isoform in the brain. A comparison of "brain-wide" vs cell type-specific CRD-NRG1 overexpressing mice revealed that pathogenic CRD-NRG1 signals for ventricular enlargement and neuroinflammation originate outside glutamatergic neurons and suggests a subcortical function of CRD-NRG1 in the control of body weight. Embryonic onset of CRD-NRG1 in glutamatergic cortical networks resulted in reduced inhibitory neurotransmission and locomotor hyperactivity. Our findings identify ventricular enlargement and locomotor hyperactivity, 2 main endophenotypes of schizophrenia, as specific consequences of spatiotemporally distinct expression profiles of hyperactivated CRD-NRG1 signaling.

Chronic Psychosocial Stress Causes Increased Anxiety-Like Behavior and Alters Endocannabinoid Levels in the Brain of C57Bl/6J Mice.

Introduction: Chronic stress causes a variety of physiological and behavioral alterations, including social impairments, altered endocrine function, and an increased risk for psychiatric disorders. Thereby, social stress is one of the most effective stressful stimuli among mammals and considered to be one of the major risk factors for the onset and progression of neuropsychiatric diseases. For analyzing the effects of social stress in mice, the resident/intruder paradigm of social defeat is a widely used model. Although the chronic social defeat stress model has been extensively studied, little is known about the effects of repeated or chronic social defeat stress on the endocannabinoid system (ECS). The present study aimed to understand the effects of chronic social stress on anxiety behavior and the levels of endocannabinoids (ECs) and two N-acylethanolamines (NAEs) in different brain regions of mice. Materials and Methods: Two-month-old, male C57Bl/6J mice were exposed to chronic psychosocial stress for 3 weeks. The effects of stress on anxiety behavior were measured using the light-dark box and hole board test. The EC levels of 2-arachidonoyl glycerol (2-AG) and anandamide (N-arachidonoylethanolamine [AEA]), as well as the levels of two NAEs (oleoylethanolamide [OEA] and palmitoylethanolamide), were analyzed by liquid chromatography-tandem mass spectrometry in the hippocampus, cerebellum, and cortex. Results: In comparison with control mice (n=12), mice exposed to social defeat stress (n=11) showed increased anxiety behaviors in the light-dark box and hole board test and gained significantly more weight during the experimental period. Additionally, chronic social stress induced differential alterations in the brain levels of 2-AG and AEA. More precisely, 2-AG levels were higher in the cortex and cerebellum, whereas reduced AEA levels were found in the hippocampus. Furthermore, we observed lower OEA levels in the hippocampus. Conclusion: The current study confirms that the ECS plays an essential role in stress responses, whereby its modulation seems to be brain region dependent.

Real-world effectiveness of abobotulinumtoxinA (Dysport®) in adults with upper limb spasticity in routine clinical practice: an observational study.

AbobotulinumtoxinA (aboBoNT-A, Dysport®) is used in clinical practice as a well-tolerated and effective therapy for muscle spasticity. AboBoNT-A has been shown to reduce upper and lower limb spastic paresis in clinical trials, demonstrating improvements in muscle tone and limb function. This open-label, multicentre, observational, non-interventional study was the first to investigate aboBoNT-A's efficacy in adult patients with upper limb spasticity (ULS) in routine clinical practice in Poland. All enrolled patients received ≥1 aboBoNT-A injection cycles, per routine clinical practice (full analysis set, FAS), and ≥1 rehabilitation session. Patients attended a baseline visit (V1) and two follow-up visits (V2, V3) for retreatment, depending on the investigator's assessment of individual patient needs, with a mean interval (SD) between injections of 4.4 (1.4) and 4.5 (1.2) months. The primary effectiveness endpoint was patient- and physician-based evaluation using the Clinical Global Impression-Improvement Scale (CGII), a validated 7-point scale (1 = very much improved to 7 = very much worse) relative to baseline. CGI-I has not previously been used as a primary endpoint in studies evaluating ULS. Secondary endpoints included muscle tone in shoulder, elbow, carpal joint, and finger muscles, measured by the Modified Ashworth Scale (MAS), and muscle strength according to the Medical Research Council scale (MRC). Of 108 enrolled patients (FAS), 92 (85.2%) completed the study and 57 (52.8%) were included in the per protocol (PP) population. AboBoNT-A improved patient conditions in 96.4% and 98.6% at V2 and V3 (investigator assessment) and 92.8% and 98.6% (as reported by patient) of patients, respectively. Significant reductions in muscle tone from baseline were observed at both visits (p < 0.0001-0.0077) across muscle groups. Increased muscle strength by cumulative MRC was observed at V2 (p = 0.0566) and V3 (p = 0.0282) versus baseline. Safety was consistent with the known profile of aboBoNT-A. In conclusion, aboBoNT-A treatment is beneficial in patients with post-stroke ULS in routine clinical practice, assessed by patients and investigators.

Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice.

Enhanced NRG1-ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway-directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell-based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1-ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to assess secondary compound actions. Transgenic mice overexpressing Nrg1 type III display cortical Erbb4 hyperphosphorylation, a condition observed in postmortem brains from schizophrenia patients. Spironolactone treatment reverted hyperphosphorylation of activated Erbb4 in these mice. In behavioral tests, spironolactone treatment of Nrg1 type III transgenic mice ameliorated schizophrenia-relevant behavioral endophenotypes, such as reduced sensorimotor gating, hyperactivity, and impaired working memory. Moreover, spironolactone increases spontaneous inhibitory postsynaptic currents in cortical slices supporting an ERBB4-mediated mode-of-action. Our findings suggest that spironolactone, a clinically safe drug, provides an opportunity for new treatment options for schizophrenia.

Molecular Signatures of Psychosocial Stress and Cognition Are Modulated by Chronic Lithium Treatment.

Chronic psychosocial stress is an important environmental risk factor of psychiatric diseases such as schizophrenia. Social defeat in rodents has been shown to be associated with maladaptive cellular and behavioral consequences including cognitive impairments. Although gene expression changes upon psychosocial stress have been described, a comprehensive transcriptome profiling study at the global level in precisely defined hippocampal subregions which are associated with learning has been lacking. In this study, we exposed adult C57Bl/6N mice for 3 weeks to "resident-intruder" paradigm and combined laser capture microdissection with microarray analyses to identify transcriptomic signatures of chronic psychosocial stress in dentate gyrus and CA3 subregion of the dorsal hippocampus. At the individual transcript level, we detected subregion specific stress responses whereas gene set enrichment analyses (GSEA) identified several common pathways upregulated upon chronic psychosocial stress related to proteasomal function and energy supply. Behavioral profiling revealed stress-associated impairments most prominent in fear memory formation which was prevented by chronic lithium treatment. Thus, we again microdissected the CA3 region and performed global transcriptome analysis to search for molecular signatures altered by lithium treatment in stressed animals. By combining GSEA with unsupervised clustering, we detected pathways that are regulated by stress and lithium in the CA3 region of the hippocampus including proteasomal components, oxidative phosphorylation, and anti-oxidative mechanisms. Our study thus provides insight into hidden molecular phenotypes of chronic psychosocial stress and lithium treatment and proves a beneficial role for lithium treatment as an agent attenuating negative effects of psychosocial stress on cognition.

Data calibration and reduction allows to visualize behavioural profiles of psychosocial influences in mice towards clinical domains.

Psychosocial stress-particularly in combination with genetic vulnerability-is a critical environmental risk factor for psychiatric diseases in humans. Isolation rearing (IR) and social defeat (SD) paradigms model psychosocial risk factors in rodents, while enriched environment (EE) protects them from behavioural deficits. Studying the influence of various environmental conditions, e.g., on genetic mouse models can help to dissect the complex gene-environment relationships underlying human psychiatric diseases. Such studies may require analysing multiple mouse cohorts; however, the comparability of behavioural experiments is challenging and often compromised by practical limitations such as group sizes and influences of handling. Therefore, protocol standardization as well as appropriate statistical normalization is necessary to compare different experiments. In this study, we analysed two independent cohorts to compare the behavioural profiles of wild-type male mice subjected to IR and SD. In both cases, EE conditions served as a reference. Multivariate statistics was applied to merge the data from individual measures into broader categories (such as curiosity, anxiety and fear memory) by estimating their calibrated joint effect within a category. Plotting and overlaying these calibrated effect sizes in a single graph allowed intuitive comparison of IR and SD behavioural profiles. This approach allows analysing multiple behavioural tests at once, which is more relevant to psychiatric syndromes than focusing on single behavioural measures. Our method revealed that motivation and fear memory are impaired by both conditions, whereas ambulation and pain sensitivity are affected only by IR and curiosity is mainly diminished upon SD. Thus, IR could be a paradigm of choice in studies focusing on positive symptoms, while SD might be more relevant for negative and cognitive symptoms.

Mice lacking the circadian modulators SHARP1 and SHARP2 display altered sleep and mixed state endophenotypes of psychiatric disorders.

Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2.

Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity.

Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect.

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective.

Schizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits. Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4). Haploinsufficiency of the TCF4 (formatting follows IUPAC nomenclature: TCF4 protein/protein function, Tcf4 rodent gene cDNA mRNA, TCF4 human gene cDNA mRNA) gene causes the Pitt-Hopkins syndrome-a neurodevelopmental disease characterized by severe mental retardation. Accordingly, Tcf4 null-mutant mice display developmental brain defects. TCF4-associated risk alleles are located in putative coding and non-coding regions of the gene. Hence, subtle changes at the level of gene expression might be relevant for the etiopathology of schizophrenia. Behavioural phenotypes obtained with a mouse model of slightly increased gene dosage and electrophysiological investigations with human risk-allele carriers revealed an overlapping spectrum of schizophrenia-relevant endophenotypes. Most prominently, early information processing and higher cognitive functions appear to be associated with TCF4 risk genotypes. Moreover, a recent human study unravelled gene × environment interactions between TCF4 risk alleles and smoking behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental, and, possibly, plasticity-related transcriptional programs in the CNS and changes of TCF4 expression also appear to affect brain networks important for information processing. Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis for identifying the underlying molecular mechanisms.

Deficits in trace fear memory in a mouse model of the schizophrenia risk gene TCF4.

The basic helix-loop-helix (bHLH) transcription factor TCF4 was confirmed in the combined analysis of several large genome-wide association studies (GWAS) as one of the rare highly replicated significant schizophrenia (SZ) susceptibility genes in large case-control cohorts. Focused genetic association studies showed that TCF4 influences verbal learning and memory, and modulates sensorimotor gating. Mice overexpressing Tcf4 in the forebrain (Tcf4tg) display cognitive deficits in hippocampus-dependent learning tasks and impairment of prepulse inhibition, a well-established endophenotype of SZ. The spectrum of cognitive deficits in SZ subjects, however, is broad and covers attention, working memory, and anticipation. Collectively, these higher order cognitive processes and the recall of remote memories are thought to depend mainly on prefrontal cortical networks. To further investigate cognitive disturbances in Tcf4tg mice, we employed the trace fear conditioning paradigm that requires attention and critically depends on the anterior cingulate cortex (ACC). We show that Tcf4tg mice display deficits in recent and remote trace fear memory and are impaired at anticipating aversive stimuli. We also assessed mRNA expression of the neuronal activity-regulated gene Fos in the ACC and hippocampus. Upon trace conditioning, Fos expression is reduced in Tcf4tg mice as compared to controls, which parallels cognitive impairments in this learning paradigm. Collectively, these data indicate that the reduced cognitive performance in Tcf4tg mice includes deficits at the level of attention and behavioral anticipation.

Acute treatment with cannabinoid receptor agonist WIN55212.2 improves prepulse inhibition in psychosocially stressed mice.

Cannabis, similar to psychosocial stress, is well known to exacerbate psychotic experiences and can precipitate psychotic episodes in vulnerable individuals. Cannabinoid receptors 1 (CB1) are widely expressed in the brain and are particularly important to mediate the effects of cannabis. Chronic cannabis use in patients and chronic cannabinoids treatment in animals is known to cause reduced prepulse inhibition (PPI). Similarly, chronic psychosocial stress in mice impairs PPI. In the present study, we investigated the synergistic effects of substances modulating the CB1-receptors and chronic psychosocial stress on PPI. For this purpose, adult C57Bl/6J mice were exposed to chronic psychosocial stress using the resident-intruder paradigm. The cannabinoid receptor agonist WIN55212.2 served as a surrogate marker for the effects of cannabis in the brain. After exposure to stress mice were acutely injected with WIN55212.2 (3 mg/kg) with or without pre-treatment with Rimonabant (3 mg/kg), a specific CB1-receptor antagonist, and subjected to behavioral testing. Stressed mice displayed a higher vulnerability to WIN55212.2 in the PPI test than control animals. The effects of WIN55212.2 on PPI were antagonized by Rimonabant suggesting an involvement of CB1-receptors in sensorimotor gating. Interestingly, WIN55212.2 increased PPI in psychosocially stressed mice although previous studies in rats showed the opposite effects. It may thus be possible, that depending on the doses of cannabinoids/CB1-receptor agonists applied and environmental conditions (psychosocial stress), opposite effects can be evoked in different experimental animals. Taken together, our data imply that CB1-receptors might play a crucial role in the synergistic effects of psychosocial stress and cannabinoids in brain.

Cognitive and sensorimotor gating impairments in transgenic mice overexpressing the schizophrenia susceptibility gene Tcf4 in the brain.

BACKGROUND: The combined analysis of several large genome-wide association studies identified the basic helix-loop-helix (bHLH) transcription factor TCF4 as one of the most significant schizophrenia susceptibility genes. Its function in the adult brain, however, is not known. TCF4 belongs to the E-protein subfamily known to be involved in neurodevelopment. The messenger RNA expression of Tcf4 is sustained in the adult mouse brain, suggesting a function in the adult nervous system. Tcf4 null mutant mice die perinatally, and haploinsufficiency of TCF4 in humans causes severe mental retardation. METHODS: To investigate the possible function of TCF4 in the adult central nervous system, we generated transgenic mice that moderately overexpress TCF4 postnatally in the brain to reduce the risk of developmental effects possibly interfering with adult brain functions. Tcf4 transgenic mice were characterized with molecular, histological, and behavioral methods. RESULTS: Tcf4 transgenic mice display profound deficits in contextual and cued fear conditioning and sensorimotor gating. Furthermore, we show that TCF4 interacts with the neurogenic bHLH factors NEUROD and NDRF in vivo. Molecular analyses revealed the dynamic circadian deregulation of neuronal bHLH factors in the adult hippocampus. CONCLUSIONS: We conclude that TCF4 likely acts in concert with other neuronal bHLH transcription factors contributing to higher-order cognitive processing. Moderate transcriptional deregulation of Tcf4 in the brain interferes with cognitive functions and might alter circadian processes in mice. These observations provide insight for the first time into the physiological function of TCF4 in the adult brain and its possible contributions to neuropsychiatric disease conditions.